Analgesic-antitumor peptide inhibits angiogenesis by suppressing AKT activation in hepatocellular carcinoma
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Hepatocellular carcinoma (HCC) is one of leading causes of cancer-related death, and its increasing incidence worldwide is a cause for concern. The recombinant analgesic-antitumor peptide (rAGAP), a protein consisting of small ubiquitin-related modifier linked with a hexa-histidine tag, exhibited the antitumor activity in HepG2 tumors in our previous study. However, the underlying molecular mechanism of its antitumor activity was still elusive. In this work, we found that treatment with rAGAP reduced phosphorylation of AKT at non-toxic doses in HepG2 cells in vitro. More importantly, treatment of HepG2 cells with rAGAP downregulated protein expression of HIF-1α, suppressed activities of HIF, reduced secretion of VEGF and IL-8, and suppressed HepG2-induced tube formation by HUVEC, which was reversed by co-incubation with SC-79 (an AKT activator). Furthermore, in tumors of athymic mice with HepG2, treatment with rAGAP reduced phosphorylation of AKT, downregulated protein expression of HIF-1α and VEGF, and microvessel density marked by positive CD31 staining. Collectively, rAGAP inhibited angiogenesis by suppressing AKT activation, which partly explained its antitumor activity in HCC.
KeywordsRecombinant analgesic-antitumor peptide HepG2 Angiogenesis AKT Hepatocellular carcinoma
Hypoxia-inducible factor 1 alpha
Human umbilical vein endothelial cells
Recombinant antitumor-analgesic peptide
Vascular endothelial growth factor
Conception and design of the experiments: QC, WL, JZ, PC. Collection, analysis, and interpretation of data: QC, WL, TZ, YL, XC, JZ, PC. Drafting the article: QC, WL, JZ, PC.
This study was supported by the project of Quality guarantee system of Chinese Herbal Medicines (201507002), the National Natural Science Foundation of China (81622048, 81473377), China Postdoctoral Science Foundation (2016M601609), and Science Foundation for Distinguished Young Scholars of Jiangsu Province (BK20140049).
Compliance with ethical standards
Conflict of interest
We declare that we have no conflict of interest.
- 3.Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, Jafri W, Payawal DA, Ohki T, Ogasawara S, Chen PJ, Lesmana CRA, Lesmana LA, Gani RA, Obi S, Dokmeci AK, Sarin SK (2017) Asia–Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int 11:317–370CrossRefGoogle Scholar
- 5.Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359:378–390CrossRefGoogle Scholar
- 13.Cao Q, Lu W, Cai X, Hu C, Wang C, Ye J, Yan H, Yang Y, Wang Z, Huo J, Liu Y, Yu Y, Ling C, Cao P (2015) In vitro refolding and functional analysis of polyhistidine-tagged Buthus martensii Karsch antitumor-analgesic peptide produced in Escherichia coli. Biotechnol Lett 37:2461–2466CrossRefGoogle Scholar
- 18.Luo D, Wang Z, Wu J, Jiang C, Wu J (2014) The role of hypoxia inducible factor-1 in hepatocellular carcinoma. Biomed Res Int 2014:409272Google Scholar
- 21.Li W, Tan D, Zhang Z, Liang JJ, Brown RE (2008) Activation of Akt-mTOR-p70S6K pathway in angiogenesis in hepatocellular carcinoma. Oncol Rep 20:713–719Google Scholar
- 23.Du J, Wang R, Yin L, Fu Y, Cai Y, Zhang Z, Liang A (2018) B < i> m</i> K CT enhances the sensitivity of temozolomide-induced apoptosis of malignant glioma U251 cells < i> in vitro</i> through blocking the AKT signaling pathway. Oncol Lett 15:1537–1544.Google Scholar
- 25.Lau CK, Yang ZF, Ho DW, Ng MN, Yeoh GC, Poon RT, Fan ST (2009) An Akt/hypoxia-inducible factor-1alpha/platelet-derived growth factor-BB autocrine loop mediates hypoxia-induced chemoresistance in liver cancer cells and tumorigenic hepatic progenitor cells. Clin Cancer Res 15:3462–3471CrossRefGoogle Scholar